Inflammasomes in Inflammation-Induced Cancer

Abstract

The inflammasome is an important multiprotein complex that functions during inflammatory immune responses. The activation of inflammasome will lead to the autoactivation of caspase-1 and subsequent cleavage of proIL-1β and proIL-18, which are key sources of inflammatory manifestations. Recently, the roles of inflammasomes in cancers have been extensively explored, especially in inflammation-induced cancers. In different and specific contexts, inflammasomes exhibit distinct and even contrasting effects in cancer development. In some cases, inflammasomes initiate carcinogenesis through the extrinsic pathway and maintain the malignant cancer microenvironment through the intrinsic pathway. On the contrary, inflammasomes also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions. The phases and compartments in which inflammasomes are activated strongly influence the final immune effects. We systemically summarize the functions of inflammasomes in inflammation-induced cancers, especially in gastrointestinal and skin cancers. Besides, information about the current therapeutic use of inflammasome-related products and potential future developing directions are also introduced.

Keywords: NOD-like receptor; cancer; caspase; inflammasome; inflammation.

Figure 1

Activation of NLRP3 inflammasome. NLRP3 inflammasome can be activated in several approaches. Pathogens especially bacteria will lead to increase of DAMPs and PAMPs, which will be sensed by NLRP3 protein as well as other pattern-recognition receptors like TLRs. The recognition by TLRs will activate NF-κB pathway and allow the host cell to get into the primed state, where the translation of proinflammatory cytokines is enhanced. The open of P2X7, an ATP-gated ion channel, will lead to K⁺ efflux which can also activate NLRP3 inflammasome directly. With the presence of gap junction protein pannexin-1, the influx of DAMPs and PAMPs will also increase. For irritants with large size like MSU crystals, they will be transported through lipid vesicles and merge with lysosomes. The crystals will result in lysosomal rupture and in turn activate NLRP3 inflammasome. Moreover, the production of ROS is increased in the recognition of DAMPs and PAMPs as well as lysosomal rupture. Eventually, intensive oxidative stress also initiates the activation. Assembled NLRP3 inflammasome will cleave raw cytokine materials with activated caspase-1 and release the mature interleukin-1β (IL-1β) and interleukin-18 (IL-18) which cause inflammation and pyroptosis. DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; LRR, leucine-rich repeat; NACHT, nucleotide-binding and oligomerization domain; PYD, pyrin; CARD, caspase recruitment domain; CASP, caspase-1; ROS, reactive oxygen species.

Figure 2

Extrinsic pathway: inflammation-induced carcinogenesis. Extrinsic pathway is known as the journey from inflammation to carcinogenesis, which can be interpreted in several dimensions. ROS/RNS can directly damage DNA, which may lead to unlock of oncogenes and inhibition of cancer suppressor genes. In addition, ROS/RNS can oxidize proteins, lipids, nucleic acids, carbohydrates, and worsen the disturbed metabolism. What’s more, intermediate products modified by ROS/RNS also have strong oxidative activity to further damage the DNA. With chronic inflammation, the function of DNA repair system is likely to be impaired. When DNA damage cannot be repaired in time but instead accumulates, genomic instability may occur. If damage persists, carcinogenesis will be the destination. In the perspective of host defense, the defect of immune barriers will increase the risk of contact with carcinogens or other toxins, which also increases the production of ROS/RNS. Furthermore, inflammatory pathways like NF-κB and STAT3 are altered through the whole journey to carcinogenesis. The dysregulated inflammatory pathways are important accomplices behind the scene. ROS, reactive oxygen species; RNS, reactive nitrogen species; 4-HE, 4-hydroxy-2-non-enal.

Figure 3

Intrinsic pathway: cancer-associated inflammation. Intrinsic pathway is about the formation of cancer microenvironment. The inflammatory cancer microenvironment consists of cellular components and non-cellular components. When transformed or cancerous cells are established, immune responses are also started. Inflammasomes are activated through different mechanisms and release interleukin-1β (IL-1β) and interleukin-18 (IL-18) to initiate inflammation. Cancerous cells and stromal cells can release chemokines and lead to neutrophil infiltration. Neutrophils will in turn secret more proinflammatory cytokines including interleukins and interferons. B cells and antibodies are also observable. Regulatory T cells, TAMs, and MDSCs work together to enhance immunosuppression. The alteration of proinflammatory cytokines will lead to abnormal polarization of T helper cells. The imbalanced T helper cell population and cancer-related immune cells facilitate the cancer progression through angiogenesis, metastasis, and cancerous resistance against immune attacks. TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; CTL, cytotoxic lymphocyte.

Figure 4

Inflammasome-related inflammation-induced cancers. There are various inflammation-induced cancers associated with inflammasomes. According to their pathogenesis and precipitating factors, they can be divided into microbe related, intermediate type, and sterile inflammation related. Take male as an example, microbe-related cancers include nasopharyngeal carcinoma (EBV), Burkitt’s lymphoma (EBV), adult T cell leukemia (HTLV-1), hepatocarcinoma (HCV), and gastric cancer (Helicobacter pylori). Colitis-associated colorectal cancer is a special type between microbe-related and sterile type, since colonic microbes and abnormal immune responses both contribute to its pathogenesis. Sterile inflammation-induced cancers include skin cancer due to the overdose UBV irradiation, melanoma, and prostate cancer. LRR, leucine-rich repeat; NACHT, nucleotide-binding and oligomerization domain; PYD, pyrin; CARD, caspase recruitment domain; CASP, caspase-1; EBV, Epstein–Barr virus; HTLV-1, human T-cell leukemia virus type 1; HCV, hepatitis C virus; UVB, ultraviolet radiation B.